This invention pertains to a solid oral dosage form containing an antiviral agent and an H1 antagonist, or antihistamine. More particularly, it pertains to dual release osmotic device tablet, which provides a controlled (sustained) release of oseltamivir and a rapid (or immediate) release of an H1 antagonist.
Antihistamines, such as H1 histamine receptor antagonists (herein referred to as xe2x80x9cH1 antagonistsxe2x80x9d or xe2x80x9cantihistaminesxe2x80x9d), are used to treat seasonal allergic rhinitis (SAR) and can be used to treat nasal congestion, e.g., stuffed or blocked nasal passages. Epidemiological, biological and clinical studies have shown that viral respiratory infections before the age of 3 years play a crucial role in the later development of rhinitis and asthma. Reduction of their frequency and severity may effect the viral alteration of the pulmonary and immune systems.
A new class of specific anti-influenza agents, the neuraminidase inhibitors, has demonstrated potent inhibition of both influenza A and B viruses. Oseltamivir (OS, GS4104, EN 241104, RO 64-0796, oseltamivir phosphate, an antiviral neuraminidase inhibitor) is used for the treatment of viral infections; however, it does not treat nasal congestion. Oseltamivir is the ethyl ester prodrug of the carbocyclic transition state sialic acid analog RO 64-0802 (GS4071), a potent and selective inhibitor of influenza A and B virus neuraminidases. Oral oseltamivir was approved for treatment of acute influenza in the United States in 1999. It has demonstrated efficacy both in treating and preventing influenza illness.
For antiviral agents to be effective, they must be used within 48 hours of the onset of influenza symptoms. Antiviral agents reduce the duration of fever and illness by one to two and one-half days and also reduce the severity of some symptoms. Although, oseltamivir reduces the severity of some symptoms, it does not reduce nasal congestion or the production of excessive mucous in the respiratory tract to the same degree that an H1 histamine receptor antagonist does. Consequently, nasal congestion or the production of excessive mucous in the respiratory tract lingers in patients having been administered oseltamivir.
G. He et al. (Clin. Pharmacokinet. (December 1999), 37(6), pp. 471-484) report that oral administration of oseltamivir delivers the active antiviral RO 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible. They report that the pharmacokinetic profile of oseltamivir is simple and predictable, and that twice-daily treatment results in effective antiviral plasma concetrations over the entire administration interval. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered oseltamivir is reportedly about 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours with the dosage form used in that study. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours. Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. The pharmacokinetic profile of the active metabolite is reportedly linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500 mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration with the dosage form used in that study. At a dosage of 75 mg twice daily, the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75 mg once daily is recommended for patients with creatinine clearance  less than 30 ml/min (1.8 L/h). The pharmacokinetics in patients with influenza are reportedly qualitatively similar to those in healthy young adults.
J. Gwaltney (U.S. Pat. No. 5,240,694, No. 5,492,689, and No. 5,422,097 discloses COVAM (combined virostatic antimediator) therapy, which includes a method and compositions for the treatment of the common cold. The method requires the nasal administration of an antiviral composition, optionally containing an antihistamine, and the concurrent oral administration of at least one anti-inflammatory agent. Gwaltney does not disclose a method or composition for the effective treatment of the common cold or other viral infections wherein both the antiviral agent and the antihistamine agent are administered orally. Moreover, Gwaltney does not disclose or suggest a dual release oral solid dosage form containing oseltamivir and an H1 antagonist.
Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770, U.S. Pat. No. 4,008,719 to Theeuwes et al., U.S. Pat. No. 4,058,122 to Theeuwes et al., U.S. Pat. No. 4,116,241 to Theeuwes et al., U.S. Pat. No. 4,160,452 to Theeuwes, U.S. Pat. No. 4,256,108 to Theeuwes, and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference. In particular, tablet formulations for providing antihistamines are disclosed in U.S. Pat. No. 4,650,807 to Findlay et al., and U.S. Pat. No. 4,501,893 to Findlay et al., the entire disclosures of which are hereby incorporated by reference.
Dual release conventional sustained release dosage forms are known for the concurrent or sequential administration of two or more drugs by a single unit dosage form. To date, none of the art discloses a dual release oral dosage form that provides a controlled release of an antiviral agent and a rapid release of an H1 antihistamine, or a controlled or sustained release of oseltamivir and a rapid or immediate release of an H1 antihistamine.
While conventional sustained release dosage forms, such as described above, are effective, osmotic devices such as those described by Faour et al. (U.S. Pat. No. 6,004,582), the entire disclosure of which is hereby incorporated by reference, are particularly advantageous for delivering two different dosage forms from a single osmotic device tablet. Faour et al., however, do not disclose osmotic device formulations comprising slow release oseltamivir combined with a rapid release H1 antagonist. They also do not disclose osmotic devices that provide the specific formulations, plasma profiles or release profiles for the various different combinations claimed herein.
In one aspect, the present invention provides a dual release drug delivery system comprising:
a first composition comprising a therapeutically effective amount of oseltamivir (OS) and at least one pharmaceutical excipient; and
a different second composition comprising a therapeutically effective amount of an H1 histamine receptor antagonist;
wherein the first composition provides a controlled or sustained release of oseltamivir and the second composition provides a rapid or immediate release of an H1 histamine receptor antagonist.
Specific embodiments of the invention include those wherein: 1) the drug delivery system is selected from the group consisting of capsules containing immediate and sustained release granules, capsules containing sustained release granules and one or more immediate release tablets, capsules containing sustained release granules and powder, and extended release film or multi-layer coated tablets; 2) at least 75% of the H1 antagonist is released within about 120 minutes and at least about 70% of the oseltamivir is released within about 24 hours; 3) the first drug composition comprises at least one release rate modifier; 4) the second drug composition comprises an H1 histamine receptor antagonist and at least one pharmaceutical excipient; 5) the first and second drug compositions are in layered arrangement with respect to one another; 6) the second drug composition surrounds the first drug composition; 7) the first drug composition is included in a core and the second drug composition is included in a coat, of one or more coats, surrounding the core; 8) the drug delivery device is a capsule containing the first and second compositions, the first composition is a granulation, and the second composition is a powder, granulation or compressed tablet.
One embodiment of the invention provides an osmotic device comprising:
a core comprising a therapeutically effective amount of oseltamivir (OS) and at least one osmotic agent or osmopolymer, wherein the core provides a controlled release of OS;
a semipermeable membrane surrounding the core and having a passageway there through; and
a drug-containing coat comprising a therapeutically effective amount of an H1 antagonist and surrounding the semipermeable membrane, wherein the external coat provides a rapid release of the H1 antagonist.
Specific embodiments of the osmotic device include those wherein: 1) the osmotic device further comprises an inert water soluble coat interposed the semipermeable membrane and the drug-containing coat; 2) the osmotic device further comprises one or more other coats surrounding the core, wherein the coats are selected from the group consisting of: inert water soluble or water erodible coat, and immediate, rapid, or delayed release coat; 3) the OS is released in a controlled or sustained manner over a period of about 20-24 hours after exposure to an aqueous environment; 4) the H1 antihistamine is released over a period of about 5-120, or 15-120, or 5-60 minutes after exposure to an aqueous environment; 5) osmotic device has an OS dissolution profile and an H1 antagonist dissolution profile as described herein.
In some embodiments, the H1 antagonist is selected from the group consisting of acrivastine, astemizol, azelastine, cetirizine, ebastine, epinastine, fexofenadine, loratadine, mizolastine, norastemizol, prometazine and terfenadine.
In other embodiments, the external coat is applied by spray coating rather than by compression coating. By spray coating rather than compression coating the external coat is thinner, and therefore a smaller osmotic device is formed.
Another aspect of the invention provides a method of treating the symptoms of or of ameliorating a viral infection or a common cold. The method comprises the step of administering a dual release dosage form comprising OS and an H1 antagonist, wherein the OS is released in a sustained manner and the H1 is released rapidly.
Target therapeutic levels for the H1 antagonist are in the range of about 2 ng to about 700 ng per ml of plasma.
Target therapeutic levels for the OS are generally in the range of about 30 to about 200 ng per ml of plasma and, for the active metabolite, in the range of about 250 to about 1300 ng/ml.
Other features, advantages and embodiments of the invention will become apparent to those skilled in the art by the following description, accompanying examples.